Halo-alkoxy-hexene-ynes



Jan. 1, 1952 M. s. NEWMAN 2,581,283

HALO-ALKOXY-HEXENEYNES Original Filed May 10, 1947 2 SHEETS-I-SHEET 1 PROPARGYL ALCOHOL-FBUTYLMAGNESIUM CHLORIDE-+- 4-METHOXYBUTANONE -2 HYDROLYZED WITH AMMONIUM CHLORIDE SOLUTION- SERARATED-CONCENTRATED AND DISTILLED.

- I I METHOXY 4 METHYLHEXYNE 2- DIOL I, 4i I DISSOLVED IN PYRIDlNE-ACETIC ANHYDRIDE ADDED-DISTILLED- l-ACETOXY -4 HYDROXY -6M ET HOXY I MIXED WITH CRUSHED POTASSIUM 1 ACID SULPHATE- DISTILLED FRACTIONATED ADDED TO SOLUTION OF SODIUM METHOXIDE IN ABSOLUTE METHANOL-ORGANIC PRODUCT ISOLATED.

| lHYDROXY-6 METHOXY 4 -METHYLHEXENE-4-YNE I DISSOLVED IN PYRIDINE AND ADDED TO SOLUTION OF THIONYL CHLORIDE IN PYRlDINE-HEATED-POURED INTO WATER- DISTILLED UNDER REDUCED PRESSURE. ICHLORO6-METHOXY-4-METHYLHEXENE-4YNE-Ej 4'-METHYLHEXYNE 2. j

I DISSOLVED WITH SODIUM IODIDE IN DISSOLVED WITH SODIUM ACETONE-STIRRED-REFLUXED BROMIDE IN METHANOL- FILTERED-CONCENTRATED SOLVENT REMOVED- EXTRACTED WITH ETHER- EXTRACTED WITH ETHER- WASHED-DRIED-DISTILLED. WASHED-DRIED-DISTILLED.

I l- IODO-6- METHOXY 4 I-BROMO-G-METHOXY "4 METHYLHEXENE-4 -YNE 2 METHYLHEXENE -4 YNE 2 FlG.l

INVENTOR. MELVIN SPENCER NEWMAN Mad/6 X HIS ATTORNEY Jan. 1, 1952 M. s. NEWMAN 2,531,283

HALO-ALKOXY-HEXENE-YNES Original Filed May 10, 1947 l 2 $HEETS-SHEET 2 FIG. 2

c n 3 X-CH2- czcc CH-CH, OCH a FIG. 3

FIG. 4

C H3 ICH -C CC =CH-CH OCH FIG. 8.

. B cH fi-O-CH -cgc-Cll -CH -CH OCH O OH FIG. 9

I INVENTOR. MELVIN SPENCER NEWMAN I ivy HIS ATTORNEY Patented Jan. 1, 1952 2,581,283 HALO-ALKOXY-HEXENE-YNES Melvin S. Newman, Columbus, Ohio, assignor to The Ohio State University Research Foundation, Columbus, Ohio, a corporation'of Ohio Original application Ma 1950, Serial No. 171,744

This application is a divisional application of my copending application Serial No. 747,177, filed May 10, 1947.

This invention relates to new compounds or compositions of matter useful as intermediates in the synthetic production of vitamin A ethers and similar compounds and to processes for synthesizing such new compounds. It is illustrated by processes of forming a 1-hydroxy-6-alkoxy-4-methylhexene4-yne-2'andits organic and halogen acid esters. Examples of such organic acid esters are the acetate, propionate, butyrate, trimethylacetate and benzoate. Examples of such halogen acid esters are 1-chloro-6 methoxy-4-methylhexene-4-yne-2, 1-iodo-6-methoxy-4-methylhexene 4-yne-2, and 1-bromo-6-methoxy-4-methylhexene-4-yne-2.

The specific hydroxy alkoxy methylhexene-ynes which I have synthesized have all had alkoxy groups. V

By the use'of the .word. alkoxy? in. the last sentence, elsewhere in this specification. and in the claims, I mean a compound having an alkyl radical attached to the remainder of the molecule by oxygen where the alkyl group has not more than six carbon atoms and preferably not more than four carbonatoms and I so define the term alkoxy wherever used herein. Compounds having an alkyl group with more than four carbon atoms'are operative but in subsequent reactions the compounds involved may be more difiicult to handle due .to higher boiling temperatures.

Other intermediate products synthesized during one of the processes used by me in formingthe above identified hydroxy ynes include 6-methoxy-4-methy1hexyne-2-diol- 1,4 and l-acetoxy-l-hydroxy 6 methoxy 4- methylhexyne-2. Prior to my discoveries there has been no recognized method of preparing any of the compounds referred to above- Nor had these compounds been previously synthesized nor isolated.

One of the objects of my invention therefor is the production of new intermediate chemical compounds useful in the synthesizing of vitamin A ethers, similar compounds and other chemicals.

Another object of my invention is the provision of new methods of synthesizing various intermediates and other chemicals. 7

A further object of my invention is the provision of new compounds of the formula CH: Y-CHa-CEC-(2=CHCH2OR where Y represents a member of th class conalkoxy ,methylhexeney 10, 1947, Serial No. Divided and this application July 1,

15 Claims. (01. 260-614) I sisting of the hydroxyl group and esters of the hydroxyl group and R represents a lower alkyl radical having not more than six carbon atoms.

A further object of my invention is the provision ofnew methylhexene-ynes including such compounds as 1-hydroxy-6-alkoxy-4-methylhexene- 4-ynes-2 and halogenated methylheXene-ynes, and of methods for synthesizing such compounds.

Further objects and features of my invention will be apparent from the following specification and claims when considered in connection with the accompanying drawings illustrating embodiments of my invention.

In the drawings:

.Fig. 1 illustrates a method according to my invention of synthesizing some of the new compounds invented by me;

Fig. 2 shows the structural formula of a halo alkoxy methylhexene-yne which may be synlzo thesized by my processes, and which corresponds to the general formula.

I OH! XCH:-CECJJ=OHOH:OR

. where .Y is shown as X which is a halogen and R is the methyl radical;

Fig. 3 shows the structural formula of a chloro methylhexene-yne which may be synthesized by my process, and which corresponds to the formula of Fig. 2 where Xis a chlorine atom;

Fig. 4 shows the structural formula of a bromo methylhexene-yne which may be synthesized by myprocesses and which corresponds to the formula of Fig. 2 where X is a bromine atom;

Fig. 5 shows the structural formula of an iodo methylhexene-yne which may be synthesized by my processes and whichcorresponds to the formula of Fig. 2 where X is an iodine atom;

Fig. 6 shows the structural formula of a hydroxy alkoxy methylhexene-yne which may be synthesized by my processes and which corresponds to the formula whereY is the hydroxyl and R is the methyl radical;

Fig. 7 shows the structural formula of an acetoxy methoxy"methylhexene-yne'which may be synthesized by one of my processes, and which alsocorresponds to the above formula where Y is the acetoxy radical and R is the methyl radical;

Fig. 8 shows the structural formula of an acetoxy hydroxy methoxy methylhexyne which is formed as an intermediateproduct during the esters. One

the alcoholysis of a;

reacted with suitable halogen acid derivatives to form halogen esters (alkyl halide'sl'.

The 1 acyloxy 6 alkoxy 4-methylhexene- 4-yne2 is an ester of d-methylhexene--yne-Z as are also the halogen esters which may be prepared therefrom. 7 Al'- though in the process described hereinafter the alcohol is obtained from the 'acyloxy' ester, the acyloxy ester may be obtained from the alcohol if desired.

Preferably I form the acyloxy ester by dehydrating a 1-acyloXy4-hydroxy-6-alkoxy4- methylhexyne-2, although the-acyloxy ester may within the scope of my invention be formed in any other desired way andthen alcoholized according to my invention to form the l-hydroxyo-alkoxy-e methylhexene-4-yne 2.

The alcoholysis of the l-acyloxy-6-alkoxy-4- methylhexene-4-yne-2 may be accomplished by heating with a metal alcoholate in an anhydrous alcohol solution and then isolating and purifying. Preferably the metal alcoholate is prepared from the same alcohol as is used as a solvent, the metal alcoholate serving'as a catalyst to the reaction of the alcohol with the methylhex'ene-yne. For example, I may use corresponding sodium, calcium, or aluminum alcoholatcs in methanol. ethanol, a propanol or a butanol.

The halogen esters may be prepared by react ing the 1-hy'dioxy-6-alkoxy-4-methylhexene- 4-yne-2 with a halogen-containing-acid deriva-- tive such as; for example, thionyl chloride, thionyl bromide, phosphorus trichloride', phosphorus tribromide and phosphorus pentachloride in an inert solvent in the presenceofa tertiaryamine-binding agent such as pyridine; thenicelines; the lutidines, quinoline, the dialkyl anilines', or the alkyl amines. The bromides and iodides may be prepared (and in certain cases may be prepared more easily) by replacing the chlorine by bromine or iodine as, for example, by refluxing the chloride with an inorganic iodide or bromide such as sodium iodide,- potassium iodide, sodium bromide or potassium bromide in a solvent such as acetone or methanol.

The dehydration of the l-acyloxyi hydroxy 6-alkoxy-4-methylhexyne-2 to a lacyloxy-6- alkoxyi-methylhexene-4-yne-2 may be accomplished by heating with a suitable dehydrating agent, such as, for example,'potassium acid sulfate or phenyl isocyanate Or other isocyanates in a vacuum or in the absence of oxygen or in an inert atmosphere, the distillate being collected in fractions and used as such or fractionated again if desired.

The preparation of a l -acyloxy-4-hydroxy-6 alkoxyi-methylhexyne-z is not described in detail nor claimed in this application. It is so described and is claimed in copending application Serial No. 747,178, now Patent No. 2,555,362.

the l-hydroxyd allkoxyw I ,termediate. inthe drawings Fig. l

to completely disclose at least one complete example of my method of forming a 1-hydroxy-6-lower alkoxyi-methylhexene-4-yne-2 and its organic and halogen esters, I have shown below one specific method of synthesizing lhydroxyTG-methoxy-4-methylhexene leynefi .iiicluding. .jin such disclosure a specific method of forming a l-acetoxyl-hydroxy-B-methoxy-4-methylhexyne-2 as an in- This specific example is illustrated to 9, inclusive, but especially in- ,Fig. 1. The specific example, however, is merely illustrative and is not to be considered as constituting the invention covered hereby.

in general, the processes illustrated in Fig. l comprise the reaction of propargyl alcohol with butylmagnesi'um 'chloride to produce a propargyl Grignard complex; the reaction of the complex with- 4-methoxybutanone-2; the hydrolysis of the product; the acetylation thereof by the addition of acetic anhydride; the distillation of the-productthereof; the dehydration thereof by However, in order heating the product with crushed potassium acid sulfate; the distillation and fractionation of the product; the alcoholysis thereof by the addition of the-product to asolution of sodium methoxide in an. alcohol (preferably methanol) the isolation of the; organic: product; theester-ification of the product by the reaction. thereof: withv a= solutionof a thionyilhalide; the heatingthereofii the isolationthereof; and; thedistillation there-- of. I may then react the product (if not an iodide)v with a.-solution of a metallic (e. g. so. dium) iodide in. acetone, reflux the product, ex-" tract it withether, anddistill it to produc'ean iodo methylhexeneeyne. It a chloride is formed from the hydroxy alkoxy methylhexene-- yne', I may alternately react the chloride with an inorganic.v bromide: (as, for: example, sodium bromide, potassium bromide or cal-, cium bromide) in acetone to form a. bromomethylhexene-yne. If :any; oneiof several other alkoxy. butanon'es is: used as a. starting: material, different halogenated alkoxy .methylhexadiene is produced. For example, insteadof using 4'.- methoxybutanone z, anyotheralkoxy butanone or similar: butanone (such as, for. example, ethoxys. butanone, benzyloxy' butanone or cyclohexyloxy' butanone) may be used to produce useful products. The products obtained by these methods are intermediate products useful in the synthetic production of vitamin A com pounds and as intermediates for: the synthetic production oi other chemicals. -The reactions: involved in the processes illus-'- trated in-Fig} 1 areas follows:

(1) HOCBECECHI+ zcnr-"cm-cue onru or cnvi -oohz ozo mgcwzoiia oiir om om ClMgQCHq CEC-MgGl+CHsC o-om-cnz-ooni enemas BrCHrCECl=CHCHzOCHz Naol The bromide may also. be synthesized direct from the hydroxy methoxy' methylhexene-yne as follows:

The following Examples I to VI, inclusive, are presented in illustration of my invention.

EXAMPLE I I 1acetoxy-6-methoxy-4 -methylhemene-4-yne-2 A mixture of 109.5 g. (.55 mole) of l-acetoxy- 4-hydroxy-6-methoxy-4-methyl-hexyne-2 and 80 g. (.58 mole) of crushed potassium acid sulfate were placed in a distilling flask. The mixture was heated under reduced pressure until distillate was'formed. Keeping the bath temperature as low as possible 73 g. of material (B. P. 96-115 at 3 mm.) was collected. This material was fractionated through a one foot helices packed column fitted with a total reflux partial take off head. The desired product was collected at 100- 106 at 4 mm.; yield=44.5 g. (45%) n =1.4773.

AnaZysis.-Calcd. for CIOHMOBI C, 65.9; H, 7.7. Found: C, 66.1, 65.7; H, 8.0, 8.1.

The product has the following structural formula:

Preparation of EXAMPLE II To a solution of 2 g- (0.37 mole) of sodium Found: C, 68.7, 68.7;

methoxide in 100 cc. of absolute methanol was added 8.5 g. (.047 mole) of l-acetoxy-G-methoxy- 4-methylhexene-4-yne-2. The solution was refluxed for two hours. The methanol was removed under reduced pressure and the organic product isolated after dilution with water by extraction with ether. The product was obtained as a pale yellow oil; B. P. 76- 78 at 0.3 to 1 mm.; yield=5.0 g. (76%); n =1.4903.

Analysis.-Calcd. for

' The product has the following structural formula: 1

CH3 HooHr-oEo-o=oH-omocm EXAMP LE III Preparation of 1-chZoro-6-methoxy at-metfiylhemene-4-yne-2 A solution of 9.5 g. (.068 mole) of l-hydroxy- 6-methoXy-4-methylhexene-4-yne-2-o1-l in 3.1 cc. of dry pyridine was added over thirty minutes to an ice cold solution of 9.5 g. (.08 mole) of purified thionyl chloride in 3.1 cc. of dry pyridine. The solution was allowed to stand at room temperature for three hours and then heated to 50 for thirty minutes. The product was isolated after pouring the reaction mixture into water, and was obtained as a colorless. oil on distillation under reduced pressure; B. P. 51 at 0.5 mm.; yield=8.7 g. (81%); n =1.4952.

AnaZysis.-Calcd. for CaHuOCl: 7.0; Cl, 22.4. Found: CI, 22.0, 21.7. p

The product has formula:

C, 60.6; H. C, 60.1, 59.8; H, 7.1, 7.1;

the following structural EXAMPLE IV Preparation of 1-z'oio-6-metho.n1,I--v

hewene-si-yne-Z A solution of 10 g. (.063 mole) of 1-chloro-6- methoxy-4-methylhexene-4-yne-2 and 15 g. (.10 mole) of sodium iodide in 100 cc. of acetone was stirred at room temperature for two hours, and then heated to reflux for one hour. After filtration and concentration of the filtrate, the product was taken up in ether, washed, dried and distilled. There was obtained 9 g. (57%) of an orange oil; B. P. 85-87/2 mm.; (75-76" at 0.5 mm.); n =1.5647.

AnaZysz's. Calcd. for CaHuIO: C, 38.47; H, 4.4; I, 50.7. Found: C, 39.7, 39.7; H, 4.6, 4.8; I,

4 methyl- The product has the following structural formula:

CH3 IOHzOEO( J=OHCH20CHa EXAMPLE v Preparation of l-iodo-fi-methoay 4 methylhemene-4-yne-2 To a solution of 14 g. of sodium iodide in cc. of acetone was added 10.5 g. of l-chloro fi-methoxy-4-methylhexene-4-yne-2. The mixture was stirred at room temperature" for one hour and was then heated to reflux for one-half hour. The precipitated sodium chloride was removed by filtration and the organic product was isolated by vacuum distillation. The desired iodo compound was obtained as a pale yellow oil; B. P,

CsHizOz: C, 68.5; H, 8.6.

where X is a halogen atom .sents a lower alkyl radical having not'more than .six carbon atoms.

.methylhexene-i-yne-Z comprising the obtaining a solution .methylhexene-4-yne-2 in'an inert anhydrous solvent including at leastone equivalent of pyridine; solution of a halogen vs-vt at i iiimg 7 52o- 1 .5'64"2 in isa stem. The 'pi-eauct the following structural ion mun. 2

CH: 'IG-HaCEC-*(=CHGH2OCH3 EXAMPLE VI Preparation of '1 bromq=6 met1wzny 4nnethol h'erbefie-4-yne-2 A solution of 8 g. (.95 mole) of 1='chloro-6;- methoxy i-methylhexene ieyne 2- and =10 g. "(.10 mole) of sodium bromide in 100 cc. of absolute methanol was refluxed for three hours with stirring. After removal of most of the methanol under reduced pressure, the product'was taken up in ether, washed,.driedand distilled. There was obtained an orange oil; B. P. 585-61" C. at 0.5 min; yield=7 .5 g. (75%); n =l.508'8. The product has thefollowing structural formula:

While the forms of embodiments of the present invention as herein disclosed constituted prefer-red forms, it is to be understood that other forms might be adopted, all coming within the scope of the claims which follow.

I claim:

1. As a composition of matter, a'hexe'ne-yne having a general structural formula of CH: -xoin-c"zo-o'=on-omon and where R; repre- 2. As a composition of matter, a hexene-yne .having a general structural formula of where X is a halogen atom.

3. A process of forming a l-halo-fi-alkoxyisteps of of a l-hydroxy-S-alkoxyiand adding the solution to an ice cold compound selected from the class consisting of thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus tribromide, and phosphorus pentachioride dis solved in an inert anhydrous solvent including at least one equivalent of pyridine.

4. A method of producing a vitamin A ether intermediate compound comprising the steps of alcoholizing a l-acyloxy-G-alkoxy 4 methylhexene-4-yne-2, wherein the acyloxy group is derived from carboxylic acid, by mixing with it a solution of a metal alcoholate dissolved in an anhydrous alcoholic solvent of which the alcohol has not more than four carbon atoms to form a 1-hydroxy fi alkoxy-e-methylhexeneyne-2 and then replacing the hydroxyl group thus formed by a-halogenby :dissolving the 1- hydroxy-6-alkoxy-4-methylhexene-4-yne-2 and adding the solution to an ice cold solution of a halogen compound selected from the class cons'isting of thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus tribromide, and phosphorus pentachloride dissolved in an inert anhydrous solvent includingat least one equivalent of pyridine.

5. As a composition of matter, a hex'en'e-yne having a general structural formula of acetone; stirring tilli'ng.

. alcoholizing 7. As a composition of mater, a hexene-yne having 'a generalstructural formula of 8. A process of forming a 1-chloro-.6-.meth-= oxy-4-methylhexene-4-yne-2 comprising the steps of dissolving 1-hydroxy-6-methoxy-4- methylhexene-4-yne-2 in dry pyridine; adding the solution to' a cold solution of thionyrehlortde in dry pyridine; allowing the solution to stand at room temperature; heating the solution; isolating; anddistilling the product-under reduced pressure.

9. A process of producing l-iodoefi-methoxy- 4-methylhexene-4-yne-2 comprising the steps of heating a solution of l-chloro-S-methoxylmethylhexenei yne-2 in an inert anhydrous solvent consisting of a low molecular weight l'retone with-a solution ofa metall-iciodide. in an inert anhydrous solvent consisting of a low molecular weight ketone.

"1'0. A process of producingl-iodo-S-methoxy 4-methylhexene-4-yne-2 comprising the steps of mixing a 'solution oi l-chloro-o-methoxyimethy1hexene-4-yne- 2 and a metallic iodide in at room temperature; heating to .reflux; filtering; extracting; removing .the solvent; washing; drying; and distilling.

11. A process of producing l bromo 'fi-methoxy--methylhexene--yne 2 comprising the steps of mixing a solution of l-chloro-fi-methoxy-4-methylhexene-4-yne-2 and a metallic bromide in acetone; stirring at room temperature; heating to reflux; filtering; extracting; re-

moving thesolvent; washing; drying; and dis- 12. A method of producing a vitaminA ether intermediate compound comprising the steps of a l-acyloxy-fiealkoxy 4-- methylhexene--yne-Z, wherein the acyloxy group is derived from carboxylic acid by treating with a solution of a metal alcoholate dissolved'inan anhydrous alcohol'c solvent of whichfth'e' alcohol has not more than fouricarbo'n atoms, to forms. i-hydroxy-6-alkoxy-4-methylhexene-4eyne 2 and the subsequent. replacement of the hydroxyl group thus-formed by. halogen-by dissolving the 1-hydroxy 6'-alkoxy4-methylhexene --4 eyne 2 and adding the solution to antice cold solution of a halogen compound selected from the class consisting of thionyl chloride, .thionyl bromide,

phosphorous trichloride, phosphorous ti'ibromide, and phosphorous.pentachloridedissolved in an inert anhydrous solvent including'sat :least one equivalent of pyridine.

13. A method of producing a vitamin A: ether intermediate compound comprising the steps of alcoholizing .a l-acyloxy-G-alkoxy 4 methylhexene-4-yne-2, wherein the acyloxy'group is derived from carboxylic acid, with a solution of a metal alcoholate-n'n an anhydrous alcoholic solvent of which the alcohol has notmore. than four carbon atoms to form-a .1-hydroxy-6-alkoxyi-methylhexenei-yneez .and replacement of the hydroxyl thusformed by reacting "with a 10 solution of a halogen compound selected from e-1nethylhexene-4-yne2 comprising the steps the class consisting of thionyl chloride, thionyl of dehydrating a 1-acyloxy-l-hydroxy-6-methbromide, phosphorus trichloride, phosphorus trioxy--methylhexyne-2 wherein the acyloxy bromide, and phosphorus pentachloride dissolved group is derived from carboxylic acid to form a in an inert anhydrous solvent including at least 1-acyloxy-6--methoxy4-methylhexene-4-yne 2' one equivalent of pyridine. alcoholizing the resulting product by treating 14. A process of forming l-iodo-S-methoxy-- with a solution of a metal alcoholate dissolved in methylhexene-el-yne-Z comprising the steps of an anhydrous alcoholic solvent of which the dehydrating a l-acyloxy-4hydroXy-6-methoxyalcohol has not more than four carbon atoms to 4 th 1h 2 wherein the acyloxy group is 10 form 1-hydroXy-6-methoxy-4-methylhexene-4 derived from carboxylic acid by heating the 3 p ac ng the hydroxyl group thus formed hexyne with potassium acid ulfate to fo m a with halogen to obtain a solution of lcl11oro-6- acyloxy-6-niethoxy-4-methylhexene-4-yne 2; f no4./ne2; andheating alcohoiyzmg the resulting product by reacting it the solution with a solution of a rnetalhc iodide with a solution of sodium methoxide in methanol 15 in an inert anhydrous solvent consisting of a low to form a l hydroxy fi methoxy 4 methyk molecular weight ketone to produce a 1-iodo-6- hexene-4-yne-2; replacing the hydroxyl group methOxy-4"methylhexene 4'yne"z' thus formed with halogen by dissolving the 1- MELVIN SNEWMAN' hydroxy-6-methoXy-4-methy1hexene-4-yne-2 in REFERENCES CITED dry pyridine and adding the solution to a cold M solution of thionyl chloride in dry pyridine to The following references are of record in the obtain a solution of l-chloro-fi-methoxylfile of thls patent:

methylhexene--yne-2; and heating the solu- UNITED STATES PATENTS tion with a solution of a metallic iodide dissolved Number Name Date in an inert anhydrous solvent consisting of a 2,122,716 Graves July 5, 1938 law molecular Weight ketone to produce a l- 2,293,136 Woodhouse et Oct 6, 1942 iodo-G-methoxy-4-methy1hexene-4yne2. 2,359,823 Davies Oct 10, 1944 15. A process of forming l-iodo-G-methoxy- 2,441,595 Rapoport May 18 1943 

1. AS A COMPOSITION OF MATTER, A HEXENE-YNE HAVING A GENERAL STRUCTURE FORMULA OF
 8. A PROCESS OF FORMINIG A 1-CHLORO-6-METHOXY-4-METHYLHEXENE-4-YNE-2 COMPRISING THE STEPS OF DISSOLVING 1-HYDROXY-6-METHOXY-4METHYLHEXENE-4-YNE-2 IN DRY PYRIDINE; ADDING THE SOLUTION TO A COLD SOLUTION OF THIONYL CHLORIDE IN DRY PYRIDINE; ALLOWING THE SOLUTION TO STAND AT ROOM TEMPERATURE; HEATING THE SOLUTION; ISOLATING; AND DISTILLING THE PRODUCT UNDER REDUCED PRESSURE. 